Cancer of the prostate is the most commonly diagnosed cancer in men and is the second most common cause of cancer death (Carter, et al., 1990; Armbruster, et al., 1993). If detected at an early stage, prostate cancer is potentially curable. However, a majority of cases are diagnosed at later stages when metastasis of the primary tumor has already occurred (Wang, et al., 1982). Even early diagnosis is problematic because not all individuals who test positive in these screens develop cancer. Present treatment for prostate cancer includes radical prostatectomy, radiation therapy, or hormonal therapy. No systemic therapy has clearly improved survival in cases of hormone refractory disease. With surgical intervention, complete eradication of the tumor is not always achieved and the observed re-occurrence of the cancer (12-68%) is dependent upon the initial clinical tumor stage (Zietman, et al., 1993). Thus, alternative methods of treatment including prophylaxis or prevention are desirable.
Prostate specific antigen (PSA) is a 240 amino acid member of the glandular kallikrein gene family. (Wang, et al., 1982; Wang, et al., 1979; Bilhartz, et al., 1991). PSA is a serine protease, produced by normal prostatic tissue, and secreted exclusively by the epithelial cells lining prostatic acini and ducts (Wang, et al., 1982; Wang, et al., 1979; Lilja, et al., 1993). Prostate specific antigen can be detected at low levels in the sera of healthy males without clinical evidence of prostate cancer. However, during neoplastic states, circulating levels of this antigen increase dramatically, correlating with the clinical stage of the disease (Schellhammer, et al., 1993; Huang, et al., 1993; Kleer, et al., 1993; Oesterling, et al., 1991). Prostate specific antigen is now the most widely used marker for prostate cancer. The tissue specificity of this antigen makes PSA a potential target antigen for active specific immunotherapy (Armbruster, et al., 1993; Brawer, et al., 1989), especially in patients who have undergone a radical prostatectomy in which the only PSA expressing tissue in the body should be in metastatic deposits. Recent studies using in-vitro immunization have shown the generation of CD4 and CD8 cells specific for PSA (Peace et al., 1994; Correale et al., 1995). However, although weak natural killer cell responses have been occasionally documented in prostate cancer patients (Choe, et al., 1987), attempts to generate an in vivo immune response have met with limited success. For example, several attempts to actively immunize patients with prostate adenocarcinoma cells admixed with Bacillus Calmette-Guerin (BCG) have shown little or no therapeutic benefit (Donovan, et al., 1990). The ability to elicit an immune response as a result of exposure to PSA in vivo would be extremely useful.
Vaccinia virus has been used in the world-wide eradication of smallpox. This virus has been shown to express a wide range of inserted genes, including several tumor associated genes such as p97, HER-2/neu, p53 and ETA (Paoletti, et al., 1993). Other pox viruses that have been suggested as useful for expression of multiple genes include avipox such as fowl pox. Cytokines expressed by recombinant vaccinia virus include IL-1, IL-2, IL-5, IL-6, TNF-.alpha. and IFN-.gamma. (Paoletti, et al., 1993). Recombinant pox viruses, for example vaccinia viruses, are being considered for use in therapy of cancer because it has been shown in animal models that the co-presentation of a weak immunogen with the highly immunogenic poxvirus proteins can elicit a strong immune response against the inserted gene product (Kaufman, et al., 1991; Paoletti, et al., 1993; Kantor, et al., 1992a; Kantor, et al., 1992b; Irvine, et al., 1993; Moss, et al., 1993). A recombinant vaccinia virus containing the human carcinoembryonic antigen gene has just completed phase 1 clinical trials in carcinoma patients with no evidence of toxicity other than that observed with the wild type smallpox vaccine (Kantor, et al., 1992b).
Currently, models for the evaluation of prostate therapeutics include the canine (McEntee, et al., 1987), and the Dunning rat (Isaacs, et al., 1986); neither of these models, however, are practical for the study of PSA-recombinant vaccines due to the very low homology of rat and canine PSA to human PSA (Karr, et al., 1995; Schroder, et al., 1982). In contrast, the prostate gland of the rhesus monkey is structurally and functionally similar to the human prostate (Wakui, et al., 1992). At the molecular level, there is 94% homology between either the amino acid or nucleic acid sequences of rhesus PSA (Gauthier, et al., 1993) and those sequences of human prostate specific antigen (Karr, et al., 1995; Lundwall, et al., 1987). Thus, human PSA is essentially an autoantigen in the rhesus monkey. Accordingly, the rhesus monkey can serve as a model for autologous anti-PSA immune reactions.